Targeting Angiogenesis and the Tumor Microenvironment Utilizing si RNA

利用 si RNA 靶向血管生成和肿瘤微环境

基本信息

批准号：
8728574
负责人：
MENASHE BARELI
金额：
$ 12.25万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-09 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728574
关键词：
Adhesions Angiogenic Factor Biological Models Cancer Patient Cells Clinical Cutaneous Melanoma Data Diagnosis Disease Down-Regulation Ectopic Expression Encapsulated Event Excision G-Protein-Coupled Receptors Genes Growth Human IL8 gene Incidence Instruction Laboratories Lecithin Lesion Life Expectancy Liposomes Lung Malignant - descriptor Melanoma Cell Messenger RNA Metastatic Melanoma Methods Modality Molecular Nanotechnology Neoplasm Metastasis Neoplasms Nude Mice Operative Surgical Procedures Organ PAR-1 Receptor Pathway interactions Patients Peptide Hydrolases Phase Phase I Clinical Trials Phenotype Platelet aggregation Play Production Proteins RNA Reporting Research Role Safety Signal Pathway Signal Transduction Skin Cancer Small Interfering RNA Staging Suggestion Surrogate Markers Therapeutic Thrombin Receptor Translating University of Texas M D Anderson Cancer Center Up-Regulation Visceral Work angiogenesis base cell type chemotherapy effective therapy improved in vivo intravenous administration irradiation lymph nodes melanoma nanoliposome nanoparticle neutralizing antibody novel therapeutics pre-clinical preclinical study receptor research clinical testing response safety testing small hairpin RNA soft tissue success tool treatment effect tumor tumor growth tumor microenvironment vector

项目摘要

2. PROJECT SUMMARY (See instructions): Melanoma is a potentially lethal neoplasm with, a propensity for acquiring the metastatic phenotype. The molecular basis for this acquisition is not very well defined and few treatment modalities are available for this neoplasm at advanced stages. Recently, we reported that one of the genes that stands out as differentially expressed in highly, metastatic melanoma cells as compared to non-metastatic cells, is the thrombin receptor PAR-1, which promotes metastases through multiple mechanisms including angiogenesis, cell signaling, and adhesion, in large part via upregulation of IL-8. Our preliminary data indicated that PAR-1 silencing by short hairpin'RNA (shRNA) in.metastatic melanoma cells inhibited their growth and metastatic potential in vivo. In this proposed study, we will advance this work to the translational phase by pursuing inhibition of PAR-1 as well as the presumed less toxic IL-8 via siRNA encapsulated in neutral liposomes to induce tumor regression in model systems. In addition, results from oUr laboratory have demonstrated that expression of the angiogenic factor interieukin 8 (IL-8), which is itself upregulated through PAR-1 signaling, correlates with the metastatic potential of melanoma cells. Moreover, using a fully human neutralizing antibody against IL-8 (ABX-IL8 which is not available for clinical use), we were able to inhibit tumor growth and metastasis of melanoma in vivo. Our hypothesis is that intravenous administration of IL-8 small interfering RNA (siRNA) packaged in neutral liposomes will cause downregulation of IL-8 /'nwVo, thereby inhibiting melanoma growth and metastasis. We will also evaluate the therapeutic strategy in melanoma patients. To these ends, we propose the following Specific Aims: Specific Aim 1: To evaluate the iri vivo effects of PAR-1 siRNA pacltaged in neutral liposomes as a possible therapeutic modality for advanced melanoma alone and/or in combination with chemotherapy. Specific Aim 2: To evaluate the in vivo effects of IL-8 siRNA packaged in neutral liposomes as a new therapeutic modality for advanced melanoma alone and/or in combination with chemotherapy. Specific Aim 3: To evaluate the safety and efficacy of IL-8 siRNA packaged in neutral liposomes (IL-8 siRNA-DOPC) in a Phase I clinical trial. This is the first attempt at using nanotechnology as a therapeutic modality for advanced melanoma.

2. 项目摘要（参见说明）：黑色素瘤是一种潜在致命的肿瘤，具有获得转移表型的倾向。这种获得的分子基础尚不十分明确，并且对于这种晚期肿瘤可用的治疗方式很少。最近，我们报道了一种突出的差异基因与非转移性细胞相比，凝血酶受体 PAR-1 在转移性黑色素瘤细胞中高度表达，它通过多种机制促进转移，包括血管生成、细胞信号传导和粘附，很大程度上是通过 IL-8 的上调。我们的初步数据表明，转移性黑色素瘤细胞中短发夹RNA (shRNA) 沉默PAR-1 可抑制其体内生长和转移潜力。在这项拟议的研究中，我们将通过封装在中性脂质体中的 siRNA 来抑制 PAR-1 以及推测毒性较低的 IL-8，以诱导模型系统中的肿瘤消退，从而将这项工作推进到转化阶段。此外，我们实验室的结果表明，血管生成因子白细胞介素 8 (IL-8) 的表达本身通过 PAR-1 信号传导上调，与黑色素瘤细胞的转移潜力。此外，使用全人源抗IL-8中和抗体（ABX-IL8，尚未用于临床），我们能够在体内抑制黑色素瘤的肿瘤生长和转移。我们的假设是静脉注射 IL-8 小干扰 RNA (siRNA) 包装在中性脂质体中会引起IL-8/'nwVo的下调，从而抑制黑色素瘤的生长和转移。我们还将评估黑色素瘤患者的治疗策略。为此，我们提出以下具体目标：具体目标 1：评估中性脂质体中的 PAR-1 siRNA 的体内效果，作为单独和/或与化疗联合治疗晚期黑色素瘤的可能治疗方式。具体目标 2：评估包装在中性脂质体中的 IL-8 siRNA 作为单独和/或与化疗联合治疗晚期黑色素瘤的新治疗方式的体内效果。具体目标 3：在 I 期临床试验中评估包装在中性脂质体中的 IL-8 siRNA（IL-8 siRNA-DOPC）的安全性和有效性。这是使用纳米技术作为晚期黑色素瘤治疗方式的首次尝试。